International Journal of Molecular Sciences
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Diversity and Function of Somatostatin-Expressing Interneurons in the Cerebral Cortex Inhibitory interneurons make up around 10–20% of the total neuron population in the cerebral cortex. A hallmark of inhibitory interneurons is their remarkable diversity in terms of morphology, synaptic connectivity, electrophysiological and neurochemical properties. It is generally understood that there are three distinct and non-overlapping interneuron classes in the mouse neocortex, namely, parvalbumin-expressing, 5-HT3A receptor-expressing and somatostatin-expressing interneuron classes. Each class is, in turn, composed of a multitude of subclasses, resulting in a growing number of interneuron classes and subclasses. In this review, I will focus on the diversity of somatostatin-expressing interneurons (SOM+ INs) in the cerebral cortex and elucidate their function in cortical circuits. I will then discuss pathological consequences of a malfunctioning of SOM+ INs in neurological disorders such as major depressive disorder, and present future avenues in SOM research and brain pathologies.
International Journal of Molecular Sciences - Tập 20 Số 12 - Trang 2952
Bioactivities of Phenolics by Focusing on Suppression of Chronic Diseases: A Review Phenolics, which are secondary metabolites of plants, exhibit remarkable bioactivities. In this contribution, we have focused on their protective effect against chronic diseases rather than their antioxidant activities, which have been widely discussed in the literature. A large body of epidemiological studies has proven the bioactivities of phenolics in both standard compounds and natural extracts: namely, anticancer, anti-inflammatory, and antibacterial activities as well as reducing diabetes, cardiovascular disease, and neurodegenerative disease. Phenolics also display anti-analgesic, anti-allergic, and anti-Alzheimer’s properties. Thus, this review provides crucial information for better understanding the bioactivities of phenolics in foods and fills a gap in the existing collective and overall knowledge in the field.
International Journal of Molecular Sciences - Tập 19 Số 6 - Trang 1573
Biological Activities and Safety of Citrus spp. Essential Oils Citrus fruits have been a commercially important crop for thousands of years. In addition, Citrus essential oils are valuable in the perfume, food, and beverage industries, and have also enjoyed use as aromatherapy and medicinal agents. This review summarizes the important biological activities and safety considerations of the essential oils of sweet orange (Citrus sinensis), bitter orange (Citrus aurantium), neroli (Citrus aurantium), orange petitgrain (Citrus aurantium), mandarin (Citrus reticulata), lemon (Citrus limon), lime (Citrus aurantifolia), grapefruit (Citrus × paradisi), bergamot (Citrus bergamia), Yuzu (Citrus junos), and kumquat (Citrus japonica).
International Journal of Molecular Sciences - Tập 19 Số 7 - Trang 1966
Suppression of GHS-R in AgRP Neurons Mitigates Diet-Induced Obesity by Activating Thermogenesis Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (AgRP-Cre;Ghsrf/f). Our data showed that GHS-R in AgRP neurons is required for ghrelin’s stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO.
International Journal of Molecular Sciences - Tập 18 Số 4 - Trang 832
NADPH Oxidase Biology and the Regulation of Tyrosine Kinase Receptor Signaling and Cancer Drug Cytotoxicity The outdated idea that reactive oxygen species (ROS) are only dangerous products of cellular metabolism, causing toxic and mutagenic effects on cellular components, is being replaced by the view that ROS have several important functions in cell signaling. In aerobic organisms, ROS can be generated from different sources, including the mitochondrial electron transport chain, xanthine oxidase, myeloperoxidase, and lipoxygenase, but the only enzyme family that produces ROS as its main product is the NADPH oxidase family (NOX enzymes). These transfer electrons from NADPH (converting it to NADP−) to oxygen to make O2•−. Due to their stability, the products of NADPH oxidase, hydrogen peroxide, and superoxide are considered the most favorable ROS to act as signaling molecules. Transcription factors that regulate gene expression involved in carcinogenesis are modulated by NADPH oxidase, and it has emerged as a promising target for cancer therapies. The present review discusses the mechanisms by which NADPH oxidase regulates signal transduction pathways in view of tyrosine kinase receptors, which are pivotal to regulating the hallmarks of cancer, and how ROS mediate the cytotoxicity of several cancer drugs employed in clinical practice.
International Journal of Molecular Sciences - Tập 14 Số 2 - Trang 3683-3704
Influence of Botanical Origin and Chemical Composition on the Protective Effect against Oxidative Damage and the Capacity to Reduce In Vitro Bacterial Biofilms of Monofloral Honeys from the Andean Region of Ecuador Three types of monofloral honey from the Andean regions of Ecuador (Avocado, Eucalyptus, and Rapeseed honey) were analyzed to determine their floral origin, physicochemical parameters, chemical composition, antioxidant capacity, and their capacity to reduce in vitro bacterial biofilms. The chemical composition varied considerably depending on floral origin. The highest values of bioactive compounds were found in Avocado honey, classified as dark amber in color, while the lowest values were found in Eucalyptus honey followed by Rapeseed honey, both classified as extra light amber. When compared to Eucalyptus and Rapeseed honey, Avocado honey showed a more effective superoxide scavenging activity, chelating metal ions capacity, and a higher ability to protect human erythrocyte membranes against lipid peroxidation. For antimicrobial activity, the hydrogen peroxide content and the capacity to inhibit the biofilm formation, and to remove preformed biofilm from Staphylococcus aureus and Klebsiella pneumoniae was determined. Avocado honey showed the highest values of hydrogen peroxide content, as well as the highest capacity to reduce in vitro bacterial biofilms. A correlation between color vs. phenolics content vs. superoxide scavenging activity vs. chelating metal ions capacity, and the capacity to protect human erythrocyte membranes against lipid peroxidation was found.
International Journal of Molecular Sciences - Tập 19 Số 1 - Trang 45
Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes’ release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs) make them suitable vehicles to pursuit this goal. AuNPs’ properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs’ role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.
International Journal of Molecular Sciences - Tập 18 Số 1 - Trang 162
Long Non-Coding RNAs as Mediators of Tumor Microenvironment and Liver Cancer Cell Communication The tumor microenvironment is an important concept that defines cancer development not only through tumor cells themselves but also the surrounding cellular and non-cellular components, including stromal cells, blood vessels, infiltrating inflammatory cells, cancer stem cells (CSC), cytokines, and growth factors, which act in concert to promote tumor cell survival and metastasis. Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Poor prognosis is largely attributable to the high rate of tumor metastasis, highlighting the importance of identifying patients at risk in advance and developing novel therapeutic targets to facilitate effective intervention. Long non-coding RNAs (lncRNA) are a class of non-protein coding transcripts longer than 200 nucleotides frequently dysregulated in various cancer types, which have multiple functions in widespread biological processes, including proliferation, apoptosis, metastasis, and metabolism. lncRNAs are involved in regulation of the tumor microenvironment and reciprocal signaling between cancer cells. Targeting of components of the tumor microenvironment or cancer cells has become a considerable focus of therapeutic research and establishing the effects of different lncRNAs on this network should aid in the development of effective treatment strategies. The current review provides a summary of the essential properties and functional roles of known lncRNAs associated with the tumor microenvironment in HCC.
International Journal of Molecular Sciences - Tập 19 Số 12 - Trang 3742
Immune Checkpoints as a Target for Colorectal Cancer Treatment Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies. We present an updated review of the biological background and clinical development of immune checkpoint inhibitors in colorectal cancer (CRC). Early trial results on PD1 and PD-L1 blockade appear promising, especially in CRC patients with microsatellite instability (MSI). Clinical trials are ongoing to confirm these preliminary results, evaluate combination strategies and identify biomarkers to predict which patients are most likely to benefit from, or show resistance to, the effects of checkpoint inhibition.
International Journal of Molecular Sciences - Tập 18 Số 6 - Trang 1324
Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It may be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context in which it occurs. Such information may positively aid drug-design. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico–chemical properties of the amino acids (native vs. mutant) can still have minimal effects on protein thermodynamics. However, if a mutation causes significant perturbation by either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize the effects of mutations on two important biophysical properties, stability and binding affinity, and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical properties.
International Journal of Molecular Sciences - Tập 20 Số 3 - Trang 548
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